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Evaluation of Mrna Contents of YBX2 and JHDM2A Genes on Testicular Tissues of Azoospermic Men with Different Classes of Spermatogenesis

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Evaluation of Mrna Contents of YBX2 and JHDM2A Genes on Testicular Tissues of Azoospermic Men with Different Classes of Spermatogenesis Original Article Evaluation of mRNA Contents of YBX2 and JHDM2A Genes on Testicular Tissues of Azoospermic Men with Different Classes of Spermatogenesis Reza Najafipour, Ph.D.1, 2, Sahar Moghbelinejad, Ph.D.1, 2*, Amir Samimi Hashjin, M.Sc.1, Farzad Rajaei, Ph.D.2, Zahra Rashvand, M.Sc.2 1. Cellular and Molecular Research Centre, Qazvin University of Medical Sciences, Qazvin, Iran 2. Department of Medical Genetics, Qazvin University of Medical Sciences, Qazvin, Iran *Corresponding Address: P.O.Box: 341197-5981, Cellular and Molecular Research Centre, Qazvin University of Medical Sciences, Qazvin, Iran Email: [email protected] Received: 27/Nov/2013, Accepted: 08/Mar/2014 Abstract Objective: Animal model studies have shown that MSY2 and JHDM2A genes have an important role in spermatogenesis process and fertility of male mice. But the potential role of these genes in human spermatogenesis and fertility is not known yet. Therefore, we evaluated expression ratios of these genes in testis tissues of men with normal and impaired spermatogenesis. Materials and Methods: In this experimental study, after RNA extraction and cDNA syn- thesis from 50 non-obstructive azoospermic and 12 normal testis tissues, the expression ratios of genes were evaluated by real time polymerase chain reaction (PCR) technique. Hematoxcylin and eosin (H&E) staining was used for histological classification of testis tis- sues. For statistical analysis, one way analysis of variance (ANOVA) test was carried out. Results: Our results showed a significant reduction in mRNA level of YBX2 in samples with impaired spermatogenesis (p<0.001) compared to samples with qualitatively nor- mal spermatogenesis and normal spermatogenesis; however, in JHDM2A gene, despite sensible reduction in gene expression level in men with impaired spermatogenesis, no significant differences were shown (p>0.05). Furthermore in YBX2, a significant negative correlation was demonstrated between the efficiency score of spermatogenesis and the threshold cycle (CT) (r=-0.7, p<0.0001), whereas in JHDM2A, this negative correlation was not significant (r=-0.4, p=0.06). Conclusion: Generally, these data indicated that YBX2 and JHDM2A genes may play an important role in male infertility, and suggested that these molecules can act as useful biomarkers for predicting male infertility. Keywords: Azoospermia, YBX2, JHDM2A Cell Journal(Yakhteh), Vol 17, No 1, Spring 2015, Pages: 121-128 Citation: Najafipour R, Moghbelinejad S, Samimi Hashjin A, Rajaei F, Rashvand Z. Evaluation of mRNA contents of YBX2 and JHDM2A genes on testicular tissues of azoospermic men with different classes of spermatogenesis. Cell J. 2015; 17(1): 121-128. Introduction mosome 17p11.2-13.1. This gene appears to be YBX2 and JHDM2A genes are germ-cell-specific testis-specific and distinct from other mammalian molecules which are essential for the production Y-box-binding proteins (3). In the mouse testis, of functional spermatozoa; therefore, their inacti- this gene is expressed from pachytene spermato- vation could lead to male infertility. Y box binding cyte to late spermatid stages, but the active form of protein 2 (YBX2), also known as Contrin, is a hu- YBX2 factor is in round spermatid stage (4). YBX2 man homologue of Xenopus DNA/RNA-binding protein is highly similar to its mouse and xenopus and mouse MSY2 proteins (1, 2). The gene encod- germ-cell Y-box protein homologues. YBX2 also ing Contrin or YBX2 is located on human chro- acts as an mRNA stabilizer and a transcription fac- CELL JOURNAL(Yakhteh), Vol 17, No 1, Spring 2015 121 mRNA Contents of YBX2 and JHDM2A on Testicular Tissue tor of some testis specific genes such asprotamine old; these patients were candidates of assisted genes. Consequently, its loss of expression is like- reproductive technique (ART) and exhibited im- ly to contribute to the nuclear condensation defects paired spermatogenesis. In 12 patients with ob- that occur in MSY2-null late-stage spermatids (4- structive azoospermia after vasectomy, biopsies 6). Histone H3 lysine 9 (H3K9) methylation is were carried out for diagnostic reasons during va- one of the best-characterized modifications in the sectomy reversal. These biopsies revealing normal study of germ cell development, such as meiotic spermatogenesis were served as controls, while the chromosomal recombination, segregation, and his- mean age of these individuals was 35 ± 2.9 years tone removal followed by chromatin condensation old. The limitation of this study was scarcity of tis- in spermiogenesis. sue samples with normal spermatogenesis, for this reason sampling time was prolonged. In order to do these processes, simultaneous function of methyltransferase and demethylase To decrease possible confounding factors, the enzymes is unavoidable (7). JmjC-containing patients were excluded for these criteria: Y chro- histone demethylase 2a (JHDM2A), also known mosome microdeletion, cystic fibrosis, varicocele, as JMJD1A or KDM3A, has been identified as Klinefelter syndrome, or exposure to chemothera- an H3K9 demethylase (for monomethylation py and radiation. In infertile patients with non-ob- and dimethylation), while it has been originally structive azoospermia, one part of testicular tissue cloned as a testis-specific gene transcript (7). specimens was used for testicular sperm extrac- Location of this gene on human chromosome tion, while the other part was cut into two pieces; is 2p11.2. JHDM2A specifically regulates the one piece was immediately prepared and frozen expression of the genes encoding transition for RNA extraction procedure, and the other piece protein 1 (Tp1) and protamine proteins, while was fixed in Bouin’s fixative (Sigma, USA) and this gene is necessary for the proper chromatin embedded in paraffin. reorganization during spermatid maturation by For histological evaluation, 5-µm-thick paraf- directly promoting the transcription of the tran- fin sections were stained in hematoxylin and eosin sition nuclear protein 1 (TNP1) and protamine1 (H&E), and then scored according to the modified (PRM 1) genes (8, 9). Since both of two candi- date genes in this research involve in expression Johnsen scoring system. In this system of classi- regulation of some testis specific and important fication, all tubular sections in each piece of the genes such as PRM1, PRM2, TNP1, TNP2, etc., testicular biopsy are evaluated systematically, and different studies have pointed out that targeting each is given a score from 1 to 10 as follows: score YBX2 and JHDM2A genes in animal models 10 including complete spermatogenesis with many causes male infertility and different degrees of spermatozoa; score 9 including slightly impaired impaired spermatogenesis. To access this fact, spermatogenesis, many late spermatids, and disor- for the first time, we evaluated the expression ganized epithelium; score 8 including less than five level of these genes in testicular tissues of men spermatozoa per tubule and few late spermatids; with non-obstructive azoospermia, with differ- score 7 including no spermatozoa, no late sperma- ent class of spermatogenesis. tids and many early spermatids; score 6 including no spermatozoa, no late spermatids and few early Materials and Methods spermatids; score 5 including no spermatozoa or spermatids and many spermatocytes; score 4 in- Testicular tissue cluding no spermatozoa or spermatids and few This experimental study was approved by the spermatocytes; score 3 including only spermato- Ethical Committee of the Faculty of Medical Sci- gonia; score 2 including no germinal cells andSer- ences of Qazvin University of Medical Sciences, toli cells only; as well as score 1 no seminiferous Qazvin, Iran. Sampling was done under supervi- epithelium (10). To follow this classifying method, sion of urologist in Fertility and Infertility Center our samples were divided into 3 main groups based of Shariati Hospital., Tehran, Iran, during 2012. on above scoring: normal spermatogenesis (score After patients gave an informed written consent, 10), qualitatively normal spermatogenesis (scores testicular biopsies were obtained from 50 azoo- 8-9), and impaired spermatogenesis (scores 1-7) spermic men with mean age of 31.3 ± 3.7 years (Table 1). CELL JOURNAL(Yakhteh), Vol 17, No 1, Spring 2015 122 Najaf ipour et al. Table 1: Characterization of patient groups I-III and results of quantitative PCR analysis Histological classification Group 1 Group 2 Group 3 Normal spermatogenesis Qualitatively normal spermatogenesis Impaired spermatogenesis Scores 10 8-9 1-7 Number of patients 12 16 34 Ct YBX2 (mean ± SD) 21.75 ± 1.2 21.2 ± 0.99 24.1 ± 1.9 Ct GAPDH (mean ± SD) 23.6 ± 0.85 23.1± 1.1 23.12 ± 2.3 2-ΔCt 3.6 ± 1.8 3.7 ± 1.5 0.5 ± 0.7 Ct JHDM2A (mean ± SD) 25.9 ± 0.96 26.33 ± 1.1 27 ± 1.7 Ct GAPDH (mean ± SD) 23.95 ± 1.5 24.3 ± 1.4 24.5 ± 1.2 2-ΔCt 0.25 ± 0.19 0.24 ± 0.15 0.17 ± 0.1 PCR: Polymerase chain reaction and SD; Standard deviation. RNA extraction and first strand cDNA synthesis minutes. Next 4 μl 5X reaction buffer for reverse transcription, 0.5 μl RiboLock™ RNase inhibi- In summary, frozen testis tissues are homog- tor, 2 μl dNTP mix and 1 μl revertaid™ H minus enized in lysis buffer (Qiagen, Germany) using reverse transcriptase (Bioneer, Korea) were add- an ultrasonic processor UP100H (100W, 30 kHz) ed to solution, and total volume reached to 25 (Hielsher, Germany), and RNA is then extracted μl with DEPC-treated water. After being centri- using RNeasy Mini Kit (Qiagen, Germany). In fuged, the solution was incubated for 60 minutes this regard, 1 volume of 70% ethanol was added at 42˚C. Ultimately the reaction was terminated to the homogenized lysate, and up to 700 μl of by heating at 70˚C for 10 minutes. the sample was then transferred to an RNeasy spin column placed in a 2 ml collection tube. We Real-time polymerase chain reaction (PCR) and used column DNase digestion to remove the re- comparative threshold cycle (CT) method sidual DNA.
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